Carcinogenicity of 1-hydroxy-3-methylcholanthrene and its electrophilic sulfate ester 1-sulfooxy-3-methylcholanthrene in Sprague-Dawley rats.
Previous experiments have demonstrated that the carcinogen 1-hydroxy-3-methylcholanthrene is a metabolite of 3-methylcholanthrene. 1-Sulfooxy-3-methylcholanthrene, prepared by chemical synthesis from 1-hydroxy-3-methylcholanthrene, was shown to be a direct acting electrophilic mutagen and DNA damaging agent. These results imply that 1-hydroxy-3-methylcholanthrene could be metabolically activated to an ultimate electrophilic and carcinogenic form of 1-hydroxy-3-methylcholanthrene and 3-methylcholanthrene in a reaction catalyzed by 3'-phosphoadenosine-5'-phosphosulfate-dependent sulfotransferase activity. 1-Hydroxy-3-methylcholanthrene and its aralkylating reactive ester, 1-sulfooxy-3-methylcholanthrene, were individually administered to groups of 12 female Sprague-Dawley rats at a 0.2 mumol dose, three times weekly, for 20 doses. 1-Sulfooxy-3-methylcholanthrene induced sarcomas at the site of injection in 8 of 12 rats (66%) by 52 weeks, whereas 1-hydroxy-3-methylcholanthrene induced sarcomas at the site of injection in 5 of 12 rats (42%) by 52 weeks. These results, taken together with the results of previous experiments, strongly support the hypothesis that the activated electrophilic mutagen 1-sulfooxy-3-methylcholanthrene plays a major role as an ultimate electrophilic and carcinogenic form of 1-hydroxy-3-methylcholanthrene, a major metabolite of 3-methylcholanthrene.
Flesher
J W
JW
Department of Pharmacology, University of Kentucky, Lexington 40536, USA. jwflesh@pop.uky.edu
Horn
J
J
Lehner
A F
AF
D000818:Animals; D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D004563:Electrochemistry; D005260:Female; D007279:Injections, Subcutaneous; D008748:Methylcholanthrene / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D009153:Mutagens / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012513:Sarcoma, Experimental / Q000139:chemically induced; D013463:Sulfuric Acid Esters / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*
D002273:Carcinogens; D009153:Mutagens; D013463:Sulfuric Acid Esters; C022236:1-hydroxy-3-methylcholanthrene; D008748:Methylcholanthrene; C099396:1-sulfooxy-3-methylcholanthrene